The invention relates to methods and compositions for the sustained release delivery of biologically active agents.
Polymeric materials have been widely used for manufacturing of medical devices, such as artificial organs, implants, medical devices, vascular prostheses, blood pumps, artificial kidney, heart valves, pacemaker lead wire insulation, intra-aortic balloon, artificial hearts, dialyzers and plasma separators, among others. The polymer used within a medical device must be biocompatible (e.g., must not produce toxic, allergic, inflammatory reactions, or other adverse reactions). It is the physical, chemical and biological processes at the interface, between the biological system and the synthetic materials used, which defines the short- and long-term potential applications of a particular device. In general, the exact profile of biocompatibility and biodegradation, including chemical and physical/mechanical properties i.e., elasticity, stress, ductility, toughness, time dependent deformation, strength, fatigue, hardness, wear resistance, and transparency for a biomaterial are extremely variable. To produce the desired properties, polymer blends produced through mixing, have been utilized. However, polymer mixing reduces entropy and induces phase separation. Thus, thermodynamic compatibility becomes an important factor for the functionality and stability of the polymer blend system.
The appropriate biological response to the surface of a device is crucial for biocompatibility. A practical approach taken towards the development of biomedical devices has involved the utilization of polymeric materials that satisfy the bulk material criteria for the device, while applying some form of surface modification. The ideal surface modification specifically tailors the biological surface properties and produces minimal change to the bulk character. Such an approach has advantages over grafting biologically active agents to the bulk polymer chains, since the latter approach brings about significant changes to the physical structure of the polymers. Methods that have been used for the surface modification of polymer surfaces, rather than bulk grafting of the polymers, have included the following: non-covalent coatings (with and without solvent), chemical surface grafting, ion implantation, Langmuir-Blodgett Overlayer and self assembled films, surface modifying additives, surface chemical reactions, and etching and roughening.
The polymeric coating of a medical device may also serve as a repository for delivery of a biologically active agent. Where the active agent is a pharmaceutical drug, it is often desirable to release the drug from the medical device over an extended period of time. Most systems for kinetically controlled direct drug delivery employ a polymer. For example, the agent may be released as the polymer enzymatically degrades or disintegrates in the body or may diffuse out of the polymeric matrix at a controlled rate. A site-specific drug transfer system can produce a high concentration of agent at the treatment site, while minimizing the adverse effects associated with systemic administration.
A polymeric system being used to control release of the drug must be free of impurities that trigger adverse biological responses (i.e., biologically inert), must produce the desired release profile, and must possess the mechanical properties required of the medical device.
In most cases biologically active agents are simply mixed with a polymer platform in a suitable solvent system. The biologically active agent is then released by particle dissolution or diffusion (when the non-bioerodable matrices are used) or during polymer breakdown (when a biodegradable polymer is used). Mixing lowers the entropy and this can result in phase separation throughout the bulk polymer, compromising the physical/mechanical properties of the polymeric coating.
U.S. Pat. No. 6,770,725 describes the covalent attachment of bioactive compounds to polymers with oligofluoro end groups. This approach was used to position biologically active agents at the surface of devices, to improve the biocompatibility of the device surface by modifying the surface with oligofluoro end groups, and to enhance the thermodynamic compatibility of the polymer-bioactive compound conjugate with the base polymer. The polymers described allow the base polymer to retain its bulk properties.
Covalent conjugation is often a multi-step chemical process ending with a covalent linkage between an available functional group in the polymer and a functional group in the biologically active agent. Generally, bioactive agents (i.e., drug) are structurally modified to accomplish covalent conjugation. For some biologically active agents, such modifications may result in the loss of some of the activity of the agent, or may completely inactivate the agent, making it impossible to deliver such an agent using a conjugation strategy.
In view of the potential drawbacks to current biologically active agent localization systems, there exists a need for surface modifying drug delivery platforms which provide for delivery of biologically active agents with a defined profile of release to targeted locations. The present invention addresses these problems and offers advantages over the prior art.